Another Meta-Analysis Supports Prolonged Bivalirudin Use in STEMI, but Is Contemporary PCI Reflected?

Yet another meta-analysis has been published supporting the use of bivalirudin with a prolonged infusion over heparin in patients receiving primary PCI.

TCTMD last reported on this controversial topic only a month ago, when a meta-analysis its authors believed to be the first of its kind looking at continued bivalirudin in STEMI patients was published in JACC: Cardiovascular Interventions. The data from five trials demonstrated that bivalirudin is not only more protective against major bleeding at 30 days than its long-time predecessor heparin, but that prolonging treatment for up to 4 hours postprocedure mitigates the risk of thrombosis.

For this study, recently published online in the Journal of the American Heart Association, Gregor Fahrni, MD, and Mathias Wolfrum, MD (Oxford University Hospitals, England), and colleagues included data from six randomized trials—BRAVE 4, BRIGHT, EUROMAX, HEAT-PPCI, HORIZONS-AMI, and MATRIX—of more than 17,000 STEMI patients who were treated with either heparin or bivalirudin, with or without a prolonged infusion.

The results were in line with prior data—showing a benefit with bivalirudin over heparin in terms of major bleeding at 30 days (1.92% vs 2.93%; OR 0.65; 95% CI 0.48-0.88)—but also showed a benefit in terms of both all-cause (2.28% vs 2.74%; OR 0.81; 95% CI 0.67-0.98) and cardiac mortality (1.68% vs 2.39%; OR 0.69; 95% CI 0.55-0.87) over the same time period. Notably, cardiac mortality was measured in only 15,482 patients in five of the six trials.

Additionally, acute stent thrombosis at 24 hours was reported in more bivalirudin-treated patients than controls (0.93% vs 0.33%; OR 2.75; 95% 1.46-5.18) as measured in five studies. However, when the 1,517 patients who received prolonged bivalirudin—only three of the six studies tested this strategy—were compared with controls, there was no longer any difference in this outcome (0.26% vs 0.33%; OR 0.81; 95% CI 0.27-2.46). Rates of major bleeding were also lower in those who received continued bivalirudin compared with heparin (0.79% vs 2.92%; OR 0.28; 95% CI 0.13-0.60).

What About Radial Access?

Speaking with TCTMD, senior author Rajesh Kharbanda, MD, PhD (Oxford University Hospitals), said the study supports the use of continued bivalirudin therapy for patients undergoing primary PCI as it “addresses the concerns about acute stent thrombosis, which has always been an issue, [without the] cost of increased bleeding.”

The biggest remaining concern relates to the effects of access-site choice on major bleeding, Kharbanda said, as contemporary practice uses transradial over transfemoral PCI much more often than was done even 5 years ago. Specifically, he noted, his institution treats over 90% of STEMI patients referred for PCI transradially, and this figure ranged from 0 to 81% among the five trials from the study with information available. As vascular access has been the cause for as much as half of all major bleeding events in the past, he said, “there will be that question of whether with contemporary radial access, is the reduction in major bleeding still clinically relevant?”

However, he pointed out, “a portion of the major bleeding is not access-site related. So clearly, that’s a point that I think we still don’t really know.”

Commenting on the study, Anthony Bavry, MD, MPH (Malcom Randall VA Medical Center, Gainesville, FL), told TCTMD that “these results do not necessarily apply to procedures performed via radial access where the risk of bleeding is reduced. Other issues that could result in bias in this study is the disproportionate use of glycoprotein IIb/IIIa inhibitors between treatment arms and also the high dose of unfractionated heparin in many of the control arms.”

“Bivalirudin remains an option for anticoagulation during STEMI,” Bavry said in an email to TCTMD, but the meta-analysis does “not prove that bivalirudin with a prolonged infusion strategy post-PCI is preferential to unfractionated heparin in these patients.”

With Bivalirudin, Go Long

Nevertheless, Kharbanda said, the issue of short versus continued bivalirudin therapy has more or less been put to rest. “Given our findings, . . . up to 3 hours is what we would suggest is the safest in terms of negating the risk of stent thrombosis,” he advised, adding that while he would “never say never” about prescribing a shorter course of the antithrombin, “the data would suggest that’s not the ideal practice.”

Bavry added that he routinely uses unfractionated heparin, and only chooses “bivalirudin if there is another compelling reason to do so (ie, heparin induced thrombocytopenia).” However, if he were to use bivalirudin, he said he would prefer to stop the infusion at the end of the case, even in light of the results of this meta-analysis, citing concerns “about residual confounding . . . from glycoprotein IIb/IIIa inhibitor use, which could be driving this observed difference in bleeding.”

But compared with the substantially cheaper option of heparin at the outset, Bavry does not think the added benefit justifies using bivalirudin. “Unfractionated heparin is inexpensive, not associated with an increased risk of stent thrombosis, and has a short half-life and has a reversal agent,” he said. “At the end of the day it is hard to beat unfractionated heparin as an anticoagulant during PCI.”

On the other hand, the results suggest that bivalirudin is the “superior treatment to heparin alone with provisional GPI,” Kharbanda said. “Whichever way you look at the data, there is a signal of a reduction in mortality with bivalirudin, which comes out in our meta-analysis as well.”

But no study has done a direct comparison between bivalirudin and heparin alone, he commented, adding that future research should focus also on cost-benefit analyses reflecting current practice and contemporary data.





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  • Fahrni G, Wolfrum M, De Maria GL, et al. Prolonged high-dose bivalirudin infusion reduces major bleeding without increasing stent thrombosis in patients undergoing primary percutaneous coronary intervention: novel insights from an updated meta-analysis. J Am Heart Assoc. 2016;Epub ahead of print.

  • Kharbanda, Wolfrum, and Bavry report no relevant conflicts of interest.
  • Fahrni reports receiving fellowship grant support from the Bangerter-Rhyner-Stiftung, Freiwillige Akademische Gesellschaft Basel, and NIHR Oxford Biomedical Research Centre.